Tetraploidy-Associated Genetic Heterogeneity Confers Chemo-Radiotherapy Resistance to Colorectal Cancer Cells.

Claudia Galofré,Zeynep Yüce,Öykü Gönül Geyik,Meritxell Mollà,Jordi Camps,Carolina Parra,Antoni Castells,Elena Asensio,Jordi Saez,Thomas Ried,Darawalee Wangsa,Daniela Hirsch

doi:10.3390/cancers12051118

Abstract

Tetraploidy, or whole-genome duplication, is a common phenomenon in cancer and preludes chromosome instability, which strongly correlates with disease progression, metastasis, and treatment failure. Therefore, it is reasonable to hypothesize that tetraploidization confers multidrug resistance. Nevertheless, the contribution of whole-genome duplication to chemo-radiotherapy resistance remains unclear. Here, using isogenic diploid and near-tetraploid clones from three colorectal cancer cell lines and one non-transformed human epithelial cell line, we show a consistent growth impairment but a divergent tumorigenic potential of near-tetraploid cells. Next, we assessed the effects of first-line chemotherapeutic drugs, other commonly used agents and ionizing radiation, and found that whole-genome duplication promoted increased chemotherapy resistance and also conferred protection against irradiation. When testing the activation of apoptosis, we observed that tetraploid cells were less prone to caspase 3 activation after treatment with first-line chemotherapeutic agents. Furthermore, we found that pre-treatment with ataxia telangiectasia and Rad3 related (ATR) inhibitors, which targets response to replication stress, significantly enhanced the sensitivity of tetraploid cells to first-line chemotherapeutic agents as well as to ionizing radiation. Our findings provide further insight into how tetraploidy results in greater levels of tolerance to chemo-radiotherapeutic agents and, moreover, we show that ATR inhibitors can sensitize near-tetraploid cells to commonly used chemo-radiotherapy regimens.

Highlights

Tetraploidy, the state of having four sets of each chromosome as a consequence of whole-genome duplication (WGD), is a common feature of cancer cells [1]
To explore to what extent tetraploidy provides a selective advantage in therapy resistance, we evaluated the effect of first-line chemotherapeutic agents used in colorectal cancer (CRC) patients, i.e., 5-fluorouracil, oxaliplatin, and FOLFOX
It is well established that tetraploid cells display increased chromosome instability (CIN), which is associated with poor prognosis

Summary

Introduction

Tetraploidy, the state of having four sets of each chromosome as a consequence of whole-genome duplication (WGD), is a common feature of cancer cells [1]. WGD was suggested to act as a driver event that arises early in some cancers [6] and was shown to predict worse overall survival in different cancer types, independent of established clinical prognostic factors [7]. It is well-known that tetraploidy can be induced through different mechanisms, including cytokinesis failure, endoreduplication, mitotic slippage and, less commonly, cell fusion [8].

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